KR102587339B1 - Racemization method of enantiomers of N-[4-(1-aminoethyl)-2,6-difluoro-phenyl]- methanesulfonamide - Google Patents

Abstract

In this specification, the R-type mirror image contained in the racemic form of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide (R/S=1/1) After selective separation of the isomers, the remaining S-type enantiomer is racemized again to form the racemate of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide ( A method for converting to (R/S=1/1) is disclosed. According to the above method, the S-type enantiomer that was previously discarded can be recycled, which is economical, and the S-type enantiomer can be racemized without contamination due to material change at a higher yield than existing recycling technologies.

Description

Racemization method of enantiomers of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide )-2,6-difluoro-phenyl]- methanesulfonamide}

Disclosed herein is a novel process for racemization of enantiomers of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide.

Recently, the demand for sterically pure compounds has been rapidly increasing. One important use for these pure stereoisomers is as intermediates for synthesis in the pharmaceutical industry. For example, it is becoming increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages include fewer side effects and greater efficacy often associated with enantiomerically pure compounds.

For example, triadimenol can have four isomers: (-)-(1S,2R)-isomer, (+)-(1R,2R)-isomer and (-)-(1S,2S). )-isomers are more active than (+)-(1R,2S)-isomers, respectively. Among the four isomers of dichlorobutrazole, the (1R,2R)-isomer is known to be the most active. In addition, Etaconazole compounds (+)-(2S,4S)- and (-)-(2S,4R)-isomers are known to have higher sterilizing effects than other isomers.

Therefore, if only one highly active isomer can be selectively produced, high effects can be achieved using a small amount, and thus there is an advantage in reducing environmental pollution caused by the use of chemicals. Especially in the case of pharmaceuticals, when one isomer is toxic to the human body, it is very important to selectively manufacture only one isomer.

Vanilloid antagonists, including N -[4-(1-aminoethyl)-phenyl]-sulfonamide derivatives, have shown efficacy against the pure stereoisomer. The synthetic method for preparing a single isomer for such N -[4-(1-aminoethyl)-phenyl]-sulfonamide derivative is known as an asymmetric synthesis method using Ellman auxiliary. As examples, WO2007-133637 A2, WO2007-129188 A1, and WO2010-010934 A1 present a method of obtaining the desired stereoisomer by introducing an Ellman auxiliary and inducing asymmetric reduction using it. However, since this method can selectively obtain optical isomers depending only on the specificity of the chiral auxiliary, the mixed isomers remaining after selective separation of the optical isomers are discarded, which is inefficient and causes environmental pollution.

International Publication No. WO 2007-133637 A1 International Publication No. WO 2007-129188 A1 International Publication No. WO 2010-010934 A1 Republic of Korea Patent Publication No. 10-1410318

Accordingly, the present invention deals with N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide (INT028-), an intermediate having chirality of the new drug substance (PAC-14028). In preparing 3), the racemate of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide (R/S=1/1) After selective separation of the included R-type enantiomer, the remaining S-type enantiomer is racemized to form N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide. The purpose is to provide a new method that can convert to racemate (R/S = 1/1).

In order to achieve the above object, the present invention in one aspect,

Adding a compound of Formula 1 below to a methylene chloride solvent and adding a halogenation reagent; Adding pyridine to the solvent and reacting; and a process for racemizing N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, comprising adding a reducing agent to the solvent and reacting the solvent.

[Formula 1]

(In Formula 1, R ₁ and R ₂ are each alkyl or halogen, and R ₃ is -HNSO ₂ CH _3. )

In addition, in one aspect of the present invention, N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide is separated into optical isomers to form an R-type enantiomer (R )-N-[4-(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide; And racemizing the S-type enantiomer excluding the R-type enantiomer obtained in the above step by the racemization method, (R)-N-[4-(1-amino-ethyl)-2,6. A method for producing -difluoro-phenyl]-methanesulfonamide is provided.

The present invention uses N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide (INT028- 3) Optical purity is very important. The method according to one aspect of the present invention is a racemate of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide (R/S=1/1 ) After selective separation of the R-type enantiomer contained in ), the remaining S-type enantiomer is racemized again to N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methane sulfur. Since it can be converted to a racemic form of phonamide (R/S=1/1), the previously discarded S-type enantiomer can be recycled, making it economical. The method according to the present invention improves the low yield of 20 to 30% of the racemization process used for existing amino acids and the incompatibility of the recycling process due to impurities, with a high yield of about 50% or more without contamination due to material changes. S-type enantiomers can be racemized.

Figure 1 shows (S) produced upon separation of optical isomers from the racemate (INT028-3rac) of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide. -N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide is reused as N-[4-(1-amino-ethyl) through a recycling process. This is a diagram showing the mechanism of racemization of -2,6-difluoro-phenyl]-methanesulfonamide into a racemate (INT028-3rac).
Figure 2 shows N-[4-(1-amino-ethyl)-2 from (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide. This is a diagram showing in more detail the mechanism for producing the racemate (INT028-3rac) of ,6-difluoro-phenyl]-methanesulfonamide.

As used herein, (R)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide means corresponding to CAS No. 957103-01-4 , can be used interchangeably with the R-type isomer of INT028-3 within the specification.

As used herein, (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide refers to CAS number 1005237-71-7. , may be used interchangeably with the S-type isomer of INT028-3 within the specification.

In the present specification, the racemate of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide refers to its R-type isomer (R)-N-[4 -(1-Amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide and its S-type isomer (S)-N-[4-(1-amino-ethyl)-2,6- Difluoro-phenyl]-methanesulfonamide is a mixed optically active isomeric compound, where the mixing ratio of R-type and S-type isomers may be 1:1, and is interchanged with INT028-3rac within the specification. It can be used negatively. The racemic CAS number of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide is 1202743-51-8.

As used herein, (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridine -3-yl)-acrylamide (PAC-14028) corresponds to CAS number 1005168-10-4, meaning it has a molecular weight of 491.47 Da.

Hereinafter, an embodiment of the present invention will be described in detail.

The new drug, (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl-6-trifluoromethyl-pyridine- For the production of 3-yl)-acrylamide (PAC-14028), the intermediate R-type N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide is used. Optical purity is very important. For this purpose, a synthetic method is being developed to prepare the intermediate (R)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide with high optical purity. Even when the optical purity is high, the problem remains that the (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide remaining after separation is discarded.

Conventional racemization methods include racemization of amino acids using strong bases, and racemization methods using some aldehydes are also widely known. However, when the above methods are applied to the racemization of (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, the yield is 20-30%. It is very low, and there was a problem that it was practically impossible to apply it to the process due to increased contamination due to changes in the material, that is, generation of impurities.

Accordingly, the present invention exhibits high optical purity when applied to the racemization of (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, making it effective. The aim is to provide a racemization method applicable to the process.

One embodiment of the present invention includes the steps of placing a compound of the following formula (1) in a methylene chloride solvent and adding a halogenation reagent; Adding pyridine to the solvent and reacting; and a process for racemizing N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, comprising adding a reducing agent to the solvent and reacting the solvent.

[Formula 1]

In Formula 1, R ₁ and R ₂ according to one embodiment are each alkyl or halogen, and R ₃ is -HNSO ₂ CH ₃ . R ₁ and R ₂ in Formula 1 may specifically be halogen, and more specifically, R ₁ and R ₂ may be F.

As an example, the compound of Formula 1 is (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide.

According to one embodiment, the halogenating reagent is not limited and may include any agent that can provide a halogenating substance such as chlorine, bromine, or iodine. As a specific example, the halogenating reagent includes trichloroisocyanuric acid, N-Chlorosuccinimide, N-Bromosuccinimide, and N-iodosuccinimide ( It may be selected from the group consisting of N-iodosuccinimide).

Additionally, as an example, the reducing agent may be selected from the group consisting of Palladium on carbon (Pd/C), Lithium aluminum hydride (LAH), and Sodium borohydride (NaBH ₄ ). Specifically, in the reducing agent Pd/C, the weight ratio of palladium (Pd) to carbon (C) may be 1 to 20.

Referring to FIG. 2, when the halogenating reagent according to one embodiment is trichloroisocyanuric acid, that is, TCCA, when TCCA is added to a methylene chloride solvent, the two hydrogens in -NH ₂ of Chemical Formula 1 are each replaced with chlorine, Then, when pyridine is added to the solvent and reacted, one of the two chlorines is separated and a double bond is formed at nitrogen as shown in the second compound diagram of FIG. 2. Then, the formed double bond is converted to a single bond by a reducing agent, and hydrogen is combined again to form N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide. A racemate is formed.

As an example, the volume of the methylene chloride solvent is the weight of (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide added to the solvent. It may be 5 to 20 (v/w) times, more specifically, 10 to 15 times.

Additionally, as an example, the amount of pyridine may be 0.3 to 2.0 equivalents, more specifically, 1 to 2 equivalents, based on the compound of Formula 1 added to the solvent.

As an example, the racemization method may further include a cooling step after each reaction step. As an example, the step of adding the reducing agent and reacting may include filtering, neutralizing, and extracting the reactant to purify it, and may further include concentrating it under reduced pressure and then purifying it.

According to the method of one embodiment of the present invention described above, the S-type optical isomer of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, i.e., the formula From compound 1, the racemate of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide can be provided in high yield. In this specification, the term "high yield" is a term well known in the technical field of the present invention. As an example, the term "high yield" refers to N-[4-(1-amino-ethyl)-2,6-di Yield of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide racemate relative to the S-type optical isomer of fluoro-phenyl]-methanesulfonamide This may be 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more. Specifically, the yield of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide racemate prepared according to an embodiment of the present invention is 50% or more. It may be less than 100%.

One embodiment of the present invention is (R)-N-[4-(1-amino-ethyl)-2,6-difluoro-, which includes a recycling step through the racemization method as shown in Figure 1. A method for producing phenyl]-methanesulfonamide can be provided.

Specifically, the above production method involves separating optical isomers of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide to produce (R)-N, which is the R-type enantiomer. Obtaining -[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide; And it may include the step of racemizing the compound of Formula 1, which is an S-type enantiomer excluding the R-type enantiomer obtained in the above step, by the method described above.

In addition, as an example, the method is to re-process the N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide racemate prepared through the racemization step. It may further include the step of separating optical isomers to obtain R-type enantiomers.

As an example, the step of obtaining (R)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide includes the N-[4-(1- Any method that can obtain R-type enantiomers by separating optical isomers of amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide is not limited and may be included. A specific example may include an asymmetric synthesis method using an Ellman auxiliary.

The R-type isomer obtained by the method according to an embodiment of the present invention can be used as an intermediate to prepare the new drug described in the application by reacting with the material described in Korean Patent Publication No. 10-1410318. Therefore, in one embodiment, the present invention provides a method for producing a new drug described in Korean Patent Publication No. 10-1410318 using the R-type stereoisomer split by the method according to an embodiment of the present invention. Or it may be about a new drug manufactured by such a method.

In one embodiment of the present invention, for example, the prepared (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-3-(2-propyl A TRPV1 antagonist containing -6-trifluoromethyl-pyridin-3-yl)-acrylamide (PAC-14028) as an active ingredient can be provided. These TRPV1 antagonists can be used in pharmaceutical compositions for the prevention or treatment of the diseases described below.

Furthermore, in one embodiment of the present invention, (R)-N-[1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]- according to an embodiment of the present invention. Pain, joints, comprising 3-(2-propyl-6-trifluoromethyl-pyridin-3-yl)-acrylamide, its optical isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Inflammatory diseases, neurological disorders, HIV-related neurological disorders, nerve damage, neurodegeneration, stroke, urinary incontinence, cystitis, gastro-duodenal ulcers, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), stool urgency, stomach- Esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurogenic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, skin irritation, inflammation of the eyes or mucous membranes, hyperacusis, tinnitus, vestibular hypersensitivity, It may relate to a pharmaceutical composition for the prevention or treatment of diseases associated with pathological stimulation and/or abnormal expression of vanilloid receptors selected from the group consisting of episodic vertigo, myocardial ischemia, hair loss, hair loss, alopecia, rhinitis, and pancreatitis. there is.

In one embodiment of the invention disclosed herein, the pain is caused by osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, toothache, fibrositis, myofascial pain syndrome, back pain, migraine and other types. It may be a disease selected from the group consisting of headaches or pain related to the disease.

Hereinafter, the present invention will be described through the following examples and test examples. The examples and test examples are intended to explain the present invention in more detail, and the scope of the present invention is not limited to the scope of the following examples. In addition, it is clear that anyone skilled in the art can make various modifications and imitations within the scope of the attached patent claims without departing from the scope of the technical idea of this invention.

[Test Example 1] Racemization 1 of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide

To confirm the racemization efficiency of (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide of the method according to an embodiment of the present invention. To this end, INT-C of Figure 2, which is an intermediate for the preparation of the racemate of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, was prepared and its yield. was confirmed.

Specifically, (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide was added to a methylene chloride solvent, a halogenation reagent was added, and then the solvent was added. Epipyridine was added and reacted to prepare INT-C.

First, (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide (100 g, 0.339 mol) was added to methylene chloride (600 ml) and 0 Cooled to ℃. TCCA (64g, 0.275g) was added and filtered when the reaction was completed. Pyridine (2eq) was slowly added to the solution remaining after filtration at 0°C. When the reaction was completed, it was neutralized with 1N-HCl aqueous solution and water (200ml). Washed twice. The remaining organic solvent layer was removed with magnesium sulfate (MgSO ₄ ) and concentrated to obtain INT-C (106 g, 94%).

NMR data for structural analysis is 1H NMR spectrum (300MHz, DMSO-d ⁶ ), δ, ppm: 9.79(s, 1H), 7.60(d, j = 9.0 Hz, 2H), 3.11(s, 3H), 2.60 (s, 3H).

At this time, as shown in Table 1 below, trichloroisocyanuric acid (TCCA) was used as the halogenating reagent, and the equivalent weight of TCCA to the S-type isomer, type of base, equivalent weight to the S-type isomer, and solvent The yields of different types were compared.

trichloroisocyanuric acid (TCCA) Base menstruum Yield (INT-C) Comparative Example 1 0.7eq TEA 0.3eq CH ₂ Cl ₂ <10% Comparative example 2 1.0eq TEA 0.3eq CH ₂ Cl ₂ <10% Comparative Example 3 2.0eq TEA 0.3eq CH ₂ Cl ₂ <10% Comparative example 4 0.7eq 2N-NaOH 0.3eq CH ₂ Cl ₂ <10% Comparative Example 5 0.7eq 2N-KOH 0.3eq CH ₂ Cl ₂ <10% Comparative Example 6 0.7eq 2N-LiOH 0.3eq CH ₂ Cl ₂ <10% Comparative Example 7 0.7eq TEA 0.3eq DMF -- Comparative example 8 0.7eq TEA 0.3eq MeOH -- Comparative Example 9 0.7eq TEA 2.0eq CH ₂ Cl ₂ <10% Comparative Example 10 0.7eq NMM 0.3eq CH ₂ Cl ₂ 35% Comparative Example 11 0.7eq DIEA 0.3eq CH ₂ Cl ₂ 32% Example 1 0.7eq Pyridine 0.3eq CH ₂ Cl ₂ 50% Example 2 0.7eq Pyridine 0.6eq CH ₂ Cl ₂ 70% Example 3 0.7eq Pyridine 1.0eq CH ₂ Cl ₂ 80% Example 4 1.0eq Pyridine 1.0eq CH ₂ Cl ₂ 84% Example 5 1.0eq Pyridine 2.0eq CH ₂ Cl ₂ 94% Example 6 1.0eq Pyridine 2.0eq ClCH ₂ CH ₂ Cl 91% Comparative Example 12 1.0eq Pyridine 2.0eq DMF <10% Comparative Example 13 1.0eq Pyridine 2.0eq MeOH ---

As a result, the compound with this chemical structure was (S)-N-[4-(1-amino-ethyl)-2,6-difluoro- when the base TEA (Triethylamine) used in porous paper technology was used. Phenyl]-methanesulfonamide showed a low yield of INT-C of about 30% or less, but when pyridine was used as a base, methylene chloride (CH ₂ Cl ₂ ) and ethylene dichloride (ClCH ₂ CH ₂ Cl) solvent showed a yield of over 80%, which is meaningful for the process.

Except for the case where pyridine was used as a base and methylene chloride (CH ₂ Cl ₂ ) was used as a solvent, all yields were low, about 30% or less, or INT-C was not obtained. Even when TEA (Triethylamine), a base used in racemization of amino acids, was used in the racemization method according to the present invention, an insignificant yield of less than 10% was observed regardless of the equivalent weight of the base.

[Test Example 2] Racemization 2 of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide

Methanol (200 ml), INT-C (20 g, 0.070 mol) of Example 5 prepared in Test Example 1, and 10% Pd/C (2 g) were added to the high pressure reactor, and then stirred for 2 hours under a hydrogen pressure of 50 psi. . After the reaction was completed, it was filtered through a celite pad, the pH was adjusted to 12 with an aqueous ammonia solution, and the filtrate was concentrated. The concentrated solid was crystallized with water to obtain the desired racemic compound N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide (17.4g, 98%). .

NMR data for structural analysis is 1H NMR spectrum (300MHz, DMSO-d ⁶ ), δ, ppm: 7.10(d, j = 8.7 Hz, 2H), 4.53(br, 2 H), 4.02 (q, j = 6.6) Hz, 1H), 2.91(s, 3H), 1.26(d, j = 6.6Hz, 2H).

R/S ratio analysis according to racemization of the obtained racemic compound was analyzed by chiral HPLC analysis method according to the conditions in [Table 2] below, and the results are shown in [Table 3].

Column SHISEIDO Chiral CD-Ph S5 (4.6 Detector PDA 220nm Instrument Waters 2998 PDA Detector, Waters 1525 Pump,
Waters 2707 Autosampler Eluent 0.5M NaClO ₄ : Methanol = 70: 30 Temperature 35℃ Injection volume 5ul Flow rate 1ml/min

result R-form S-form Before reaction (INT028-3 S-form) - 100% After reaction (racemization) 49% 51%

* INT028-3 S-form: (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide

As shown in Table 3, the ratio of R-form and S-form after reaction is about 1:1, so as a result of racemization according to an embodiment of the present invention, N-[4-(1-amino-ethyl)- La of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide from the S-type isomer of 2,6-difluoro-phenyl]-methanesulfonamide It can be confirmed that the semi-sieve was produced effectively.

Claims (11)

Adding a compound of Formula 1 below to a methylene chloride solvent and adding a halogenation reagent;
Adding pyridine to the solvent and reacting; and
Adding a reducing agent to the solvent and reacting it;
Including,
The pyridine is 0.6 to 2 equivalents of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide relative to the compound of Formula 1 added to the solvent. Racemization method:
[Formula 1]

In Formula 1, R ₁ and R ₂ are each alkyl or halogen, and R ₃ is -HNSO ₂ CH ₃ . The racemization of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide according to claim 1, wherein R ₁ and R ₂ of Formula 1 are halogens. method. The racemization of N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide according to claim 1, wherein R ₁ and R ₂ of Formula 1 are F. method. The method of claim 1, wherein the compound of Formula 1 is (S)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, N-[4 Method for racemization of -(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide. The method of claim 1, wherein the halogenating reagent is trichloroisocyanuric acid, N-Chlorosuccinimide, N-Bromosuccinimide, and N-iodosuccinimide. A process for racemizing N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, which is selected from the group consisting of imide (N-iodosuccinimide). The method of claim 1, wherein the reducing agent is N-[4-(1-amino-ethyl) selected from the group consisting of Pd/C (Palladium on carbon), LAH (Lithium aluminum hydride), and NaBH ₄ (Sodium borohydride). )-2,6-Difluoro-phenyl]-methanesulfonamide racemization method. The method of claim 1, wherein the volume of the methylene chloride solvent is 5 to 20 times the weight of the compound of Formula 1 added to the solvent. Method for racemization of rho-phenyl]-methanesulfonamide. delete The method of claim 6, wherein the weight ratio of palladium (Pd) to carbon (C) in the reducing agent Pd/C is 1 to 20, N-[4-(1-amino-ethyl)-2,6-difluoro. Method for racemization of -phenyl]-methanesulfonamide. N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide was separated into optical isomers to form the R-type enantiomer (R)-N-[4-(1- Obtaining amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide; and
Racemizing the compound of Formula 1, which is an S-type enantiomer excluding the R-type enantiomer obtained in the above step, by the method according to any one of claims 1 to 7 and 9;
A method for producing (R)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, including. The method of claim 10, wherein the N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide racemate prepared through the racemization step is re-processed. (R)-N-[4-(1-amino-ethyl)-2,6-difluoro-phenyl]-methanesulfonamide, further comprising the step of separating optical isomers to obtain R-type enantiomers. Manufacturing method.